This project focuses on identifying the factors that determine human susceptibility to bioweapons agents. This is an important goal, as we need to be able to identify high-risk groups in order to target effective preventive measures. Evidence from human and animal studies supports the concept that host factors, some of which are genetically determined, are important modifiers of susceptibility to diseases such as malaria and meningococcal infection. There is considerable evidence demonstrating person to person variability in innate immune inflammatory responses to bacterial products. This variability is likely to extend to innate immune inflammatory responses to products of bacteria that may be used as bioweapons agents and could influence outcomes after exposure to such agents. An understanding of the molecular mechanisms underlying human variability in innate immune inflammatory responses to these agents may help to prospectively identify populations at high-risk for poor outcomes after a bioweapons attack. This would aid in the optimal allocation of resources and may identify new therapeutic targets. We propose to measure the variability in innate immune responses to Y. pestis and other potential bioweapons agents using an in vitro model of whole blood responses to bacterial products. We will investigate the magnitude of the genetic component of this variability through a classical twins study. We will determine the extent to which specific allelic haplotypes contribute to this variability. Finally, we will identify innate immune response profiles in patients with chronic respiratory diseases, a population that is likely to be at high-risk for poor outcomes in the event of exposure to aerosolized Y. pestis and other bioweapons agents. Our initial emphasis will be on Y. pestis, but the approaches developed in these studies will be adapted to subsequent studies of other potential bioweapons agents.